The overarching goal of the project is to discover and translate knowledge regarding the biology of pulmonary premalignancy to reduce lung cancer burden through 1) the discovery and validation of clinically useful biomarkers of risk and 2) the development of effective chemopreventive treatments. Biomarkers of lung cancer risk can have a variety of clinical uses, including population screening for early detection, defining high risk populations and as aids in guiding clinical decision making in settings of CT detected nodules of indeterminate etiology. Regardless of the outcome of ongoing randomized controlled trials of lung cancer screening using CT, there will be an increasing clinical need for risk biomarkers to guide decisions on management of lung nodules detected by CT. New knowledge regarding the biology of pulmonary premalignancy is being translated to novel chemoprevention strategies by this and other SPORE projects. Our Specific Aims are to: Specific Aim 1. Identify and validate biomarkers of lung cancer in sputum, bronchial epithelium, BAL and blood. We will focus on biomarkers with considerable preliminary support, including atypia, gene promoter hypermethylation and chromosomal aneusomy in sputum, as well as on the development of new approaches, including these same markers and protein expression in bronchial epithelium and bronchoalveolar lavage. We will take advantage of unique prospective cohorts of subjects with biological samples harvested and stored and in whom both prevalent and incident lung cancer is tracked by a team of epidemiology staff to carry out cross sectional and longitudinal nested case control studies. Specific Aim 2. Validate the clinical utility of sputum biomarkers in the context of the NLST ACRIN Trial. The most promising sputum markers from Specific Aim 1 will be validated as a complementary set of biomarkers in groups of subjects strategically defined and sampled from a trial of CT screening. Analyses will assess the performance of this biomarker panel for lung cancer screening as well as for its utility in assisting in clinical decisions regarding the management of pulmonary nodules of undetermined significance. Specific Aim 3. Conduct Phase II chemoprevention trials to prioritize agents for testing in Phase III trials. The current lloprost chemoprevention trial will be completed in early 2008. We will analyze the response and develop a successor trial based on a PPAR gamma agonist as supported by preclinical data from Project 3. Our proposal will have important implications for early detection, diagnosis and prevention of lung cancer